Protective HIV-specific CD8+ T cells evade Treg cell suppression

Specific human leukocyte antigens (HLAs), notably HLA-B* 27 and HLA-B* 57 allele groups, have long been associated with control of HIV-1. Although the majority of HIV-specific CD8(+) T cells lose proliferative capacity during chronic infection, T cells restricted by HLA-B* 27 or HLA-B* 57 allele groups do not. Here we show that CD8(+) T cells restricted by 'protective' HLA allele groups are not suppressed by T-reg cells, whereas, within the same individual, T cells restricted by 'nonprotective' alleles are highly suppressed ex vivo. This differential sensitivity of HIV-specific CD8(+) T cells to T-reg cell-mediated suppression correlates with their expression of the inhibitory receptor T cell immunoglobulin domain and mucin domain 3 (Tim-3) after stimulation with their cognate epitopes. Furthermore, we show that HLA-B* 27- and HLA-B* 57-restricted effectors also evade T-reg cell-mediated suppression by directly killing T-reg cells they encounter in a granzyme B (GzmB)-dependent manner. This study uncovers a previously unknown explanation for why HLA-B* 27 and HLA-B* 57 allele groups are associated with delayed HIV-1 disease progression.